Project summary: Failure of insulin producing beta cells in the setting of insulin resistance is the main underlying cause for type 2 diabetes mellitus. Genetic susceptibility, age, lifestyle, and environmental factors contribute to beta cell failure in type-2 diabetes mellitus. Others and we previously published studies showing that low-level chronic exposure to the non-essential transition metal cadmium (Cd) in the general population is associated with an increase in the risk of prediabetes and type 2 diabetes mellitus. In recent preliminary studies, we have shown that in vivo exposure to Cd caused a rise in blood sugar accompanied by altered insulin secretion in mice. We also found that insulin-producing pancreatic beta cells accumulate Cd avidly, leading to impaired insulin secretion and an increase in signs of endoplasmatic reticulum stress. The goal of the proposed studies is to examine the mechanism by which exposure to various, environmentally relevant concentrations of cadmium impair insulin production from beta cells. Specifically, we will build on our current preliminary data and explore the hypothesis that accumulation of Cd in insulin producing beta cells causes beta cell toxicity by impairing normal zinc medicated insulin processing with resulting accumulation of misfolded insulin and ER stress. The impact of these studies will be a mechanistic characterization of the role of low, but environmentally realistic concentrations of Cd in the development of type 2 diabetes mellitus.